Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/65—Tetracyclines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

• This invention relates to an aqueous solution containing fat-soluble vitamin K which contains specified stabilizer(s) and thus remains stable for a prolonged period of time.
• Vitamin Ks are substances which relate to blood coagulation and electron transport systems and have been widely employed clinically. Recently it is desired to provide them in the form of an aqueous solution.
• a known method for dissolving fat-soluble vitamins in water comprises using nonionic surfactants such as HCO®-60 (mfd. by Nikko Chemical K.K.).
• HCO®-60 mfd. by Nikko Chemical K.K.
• HCO-60® mfd. by Nikko Chemical K.K.
• lecithin As an emulsifier.
• the low emulsifying capability of lecithin makes it necessary to use a special device, namely, a pressure emulsifier.
• the emulsion thus obtained shows a limited stability upon prolonged storage (cf. Japanese Patent Laid-Open No. 56315/1978).
• Another known method for preparing a stable aqueous solution containing fat-soluble vitamin comprises preliminarily dispersing and solubilizing the fat-soluble vitamin in an aqueous medium by using hydrogenated lecithin.
• WO-A-8701035 discloses a pharmaceutical composition for parenteral administration in the form of a microemulsion which comprises pseudomicelles including a fat-soluble active ingredient, a naturally amphipatic substance and a hydrophobic lipid.
• the active ingredient may be a vitamin K derivative; the amphipatic substance may be a lecithin; and the hydrophobic lipid may be a triglyceride or soybean oil.
• the present inventors have attempted to solve the above mentioned problems and to provide a stable aqueous solution containing vitamin K1 or K2, namely, active fat-soluble vitamin Ks. As a result, they have completed the present invention.
• the present invention provides an aqueous solution containing fat-soluble vitamin K comprising: 0.02 to 1.5% by weight of a stabilizer selected from vegetable oil(s), glycerol fatty acid ester(s) and sorbitan fatty acid ester(s), 0.1 to 1.0% by weight of menatetrenone (vitamin K2 ) or phytonadione (vitamin K1), and 0.05 to 3% by weight of hydrogenated lecithin, the weight percentages being based on the whole aqueous solution.
• a stabilizer selected from vegetable oil(s), glycerol fatty acid ester(s) and sorbitan fatty acid ester(s)
• vitamin K1 menatetrenone
• vitamin K1 phytonadione
• this aqueous solution remains transparent or somewhat cloudy while showing little change upon prolonged storage.
• the present invention makes it possible to obtain an aqueous solution which is stable for a long time.
• the aqueous solution containing fat-soluble vitamin K of the present invention is characterized in that it shows a high residual transmittance (%), which is calculated according to an equation as will be shown below based on the transmittances at 640 nm (T640) determined immediately after the preparation and after storing at 45°C for 30 days, compared with those containing no stabilizer.
• residual transmittance (%) (T640 after storing)/ (basic T640) x 100
• stabilizer(s) are added to an aqueous solution containing vitamin K1 or K2 and hydrogenated lecithin at the following ratio.
• the aqueous solution of an active vitamin K has a concentration of 0.1 to 1.0 % by weight, usually 0.2 to 0.5 % by weight.
• concentrations of 0.5 % by weight are often employed.
• concentrations around 0.2 % by weight are often employed.
• the amount of the active vitamin Ks is not restricted thereby.
• the hydrogenated lecithin to be used in the present invention are hydrogenated soybean and yolk lecithins.
• This hydrogenated lecithin preferably comprises at least 85 % of phospholipids and at least 60 %, based on the phospholipids, of phosphatidylcholine and has an iodine number of 10 to 60, still preferably 25 to 50 (cf. Japanese Patent Laid-Open No. 62010/1980).
• the aqueous solution of the present invention contains 0.05 to 3 % by weight of the hydrogenated lecithin.
• Examples of the vegetable oils to be used in the present invention include soybean, sesame, olive, cotton seed, tsubaki, rapeseed, peanut and corn oils.
• glycerol fatty acid esters to be used in the present invention include triesters of glycerol and fatty acids having 8 to 12 carbon atoms and mono- and triesters of glycerol and oleic, stearic or palmitic acid.
• sorbitan fatty acid esters to be used in the present invention include mono-, sesqui- and triesters of sorbitan and oleic, stearic or palmitic acid.
• the amount of the stabilizer(s) selected from among said vegetable oils, glycerol fatty acid esters and sorbitan fatty acid esters may vary depending on the purpose of application of the aqueous solution to be prepared.
• the stabilizer(s) are used in an amount of 0.02 to 1.5% by weight, based on the whole aqueous solution. In practice, 0.01 to 3 parts by weight of the stabilizer(s) may be added per part by weight of the vitamin K1 or K2, though the present invention is not specifically restricted thereby.
• the amount of the stabilizer(s) is less than 0.004% by weight of the whole aqueous solution, no stabilization of the aqueous solution can be achieved.
• it exceeds 5% by weight on the other hand, the aqueous solution would become undesirably cloudy at the mixing stage.
• the aqueous solution of the present invention may be apropriately prepared.
• An example of the preperation thereof is as follows.
• purified hydrogenated yolk lecithin or purified hydrogenated soybean lecithin and a stabilizer selected from among vegetable oils, glycerol fatty acid esters and sorbitan fatty acid esters are added to vitamin K1 or K2 together with a small amount of water.
• the resulting mixture is preferably heated to 70 to 95°C and homogeneously dispersed under ultrasonic irradiation or stirring.
• the aqueous solution of the present invention can be obtained.
• the aqueous solution of the present invention When the aqueous solution of the present invention is to be used as an injection, it may be filtered, filled in an ampule and sterilized.
• the abovementioned other components may be selected from among, for example, buffers such as natural amino acids including glycine, bactericides and tonicity agents, without restriction. However it is preferable to avoid the addition of any electrolyte components, since they would inhibit the dispersion, in particular, solubilization.
• water-soluble solvent(s) such as ethanol, propylene glycol, D-sorbitol, low molecular weight polyethylene glycol or glycerol.
• these solvents are highly effective in remarkably shortening the time required for the rough dispersion of the vitamin K1 or K2 during the preparation of the aqueous solution.
• the vitamin K1 or K2 may be preliminarily dispersed in a water-soluble solvent by using the hydrogenated lecithin and then water is added thereto.
• the time required for the solubilization can be shortened, compared with the abovementioned case wherein the vitamin K1 or K2 and hydrogenated lecithin are directly mixed together and then water is added thereto.
• water-soluble solvent(s) When the water-soluble solvent(s) are to be added in order to facilitate the preparation of the aqueous solution, they may be preferably added in an amount of 1 to 50 parts by weight per part by weight of the vitamin K1 or K2. It is further preferable that 2 to 10 % by weight of said solvent(s) are contained in the aqueous solution of the present invention.
• tonicity agents commonly employed in the art, for example, sugars and/or sugar alcohols such as glucose, xylitol, sorbitol or mannitol may be added thereto. Namely, the addition of these tonicity agents would never deteriorate the effects of the present invention. The use of these additives is rather effective in order to inhibit the formation of cloudiness in the sterilization of the injection product.
• These tonicity agents may be preferably used in an amount of 1 to 10 % by weight based on the aqueous solution of the present invention.
• the mixture was filtered through a membrane filter and filled in a brown 2-ml ampoule. After purging with nitrogen, heat-sealing and free-flowing steam sterilization, the transmittance at 640 nm (T 640nm %) was determined. Then each sample was stored at 45°C for one month and the transmittance (T 640nm %) was determined again. Thus the residual transmittance was calculated.

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• Health & Medical Sciences (AREA)
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• Chemical & Material Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Molecular Biology (AREA)
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• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Dispersion Chemistry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Dermatology (AREA)
• Obesity (AREA)
• Nutrition Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
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• Organic Chemistry (AREA)
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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1988
  • 1988-07-11 JP JP63172463A patent/JPH0681739B2/ja not_active Expired - Lifetime
• 1989
  • 1989-07-07 CA CA000605121A patent/CA1340171C/en not_active Expired - Fee Related
  • 1989-07-07 US US07/376,708 patent/US5021570A/en not_active Expired - Fee Related
  • 1989-07-11 KR KR1019890009859A patent/KR920002326B1/ko not_active IP Right Cessation
  • 1989-07-11 AT AT89112662T patent/ATE74754T1/de not_active IP Right Cessation
  • 1989-07-11 EP EP89112662A patent/EP0350864B1/en not_active Expired - Lifetime
  • 1989-07-11 DE DE8989112662T patent/DE68901222D1/de not_active Expired - Fee Related

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